- Email: [email protected]
Chemotherapy for Oral Cancer
C h e m o t h e r a p y fo r O r a l Cancer Lee Hartner,
MD
KEYWORDS Chemotherapy Oral cancer Chemoradiation Cisplatin Cetuximab Nivolumab Pembrolizumab KEY POINTS Adjuvant chemotherapy has not been shown to improve treatment outcomes in patients with oral cancer after surgery and should not be used. Adjuvant combined chemotherapy and radiation improves survival for patients with extracapsular extension in nodal metastases and positive resection margins. Cisplatin should be used. Patients with oral cancer can be treated with primary chemoradiation, although the impact on survival is unclear. Cisplatin is the standard agent to combine with radiation. Cetuximab has not been well-studied. Induction chemotherapy can be used selectively, but its impact on overall survival remains unclear and is associated with significant toxicity. Anti– programmed cell death-ligand 1 antibodies have been shown to improve survival for patients with metastatic disease after treatment with platinum-based chemotherapy.
INTRODUCTION
The past several years have seen major advances in the use of systemic therapy for treatment of patients with oral cancer. Systemic therapy refers to chemotherapy and immunotherapy drugs, which are playing an increasingly important role in treatment. Chemotherapy has classically been used either as a primary treatment modality or in combination with radiation, where it is used as a radiation sensitizer. Based on the results of pivotal trials during the past decade, the use of systemic therapy has expanded in scope and has resulted in meaningful improvements in patient outcomes. This article discusses the different uses for systemic therapy in the treatment of patients with oral squamous cell carcinoma and reviews the current state of practice and areas of future investigation. In discussing studies, the relevance to patients with oral cancer are highlighted. It is important to remember that studies in patients
Conflicts of Interest: None to report. Abramson Cancer Center at Pennsylvania Hospital, 230 West Washington Square, Philadelphia, PA 19106, USA E-mail address: [email protected] Dent Clin N Am - (2017) -–http://dx.doi.org/10.1016/j.cden.2017.08.006 0011-8532/17/ª 2017 Elsevier Inc. All rights reserved.
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with squamous cell carcinoma of the head and neck include patients with different primary sites and they are not always represented in the same relative amounts. Despite that, however, the results of these studies are in most cases applied to patients with primary tumors of all different subsites. ADJUVANT CHEMOTHERAPY
The primary treatment modality for patients with oral cancer is surgery when possible without undue morbidity. Adjuvant chemotherapy is given after surgery in many types of cancer for reducing the incidence of metastatic recurrence. At the present time, adjuvant chemotherapy has no established role in the treatment of patients after surgery for oral cancer. The most recent update of a very large metaanalysis examining the role of chemotherapy in treatment of patients with head and neck cancer found no evidence of benefit.1 It included a total of 2567 patients taken from 6 studies that included patients with oral cancer. Therefore, adjuvant chemotherapy should only be used in the context of a clinical trial. ADJUVANT CHEMORADIOTHERAPY
In addition to studies of chemotherapy as a standalone adjuvant treatment modality, multiple studies have examined the use of concurrent chemotherapy and radiation. In this setting, chemotherapy is given as a radiation sensitizer with the goal of reducing radiation resistance. Multiple studies have found this approach is superior to radiation alone in patients with an increased risk of recurrence. The 2 largest trials examining this question, unfortunately, came to different conclusions. In the EORTC trial 22,931, a total of 334 patients were treated with either radiation alone or radiation combined with cisplatin 100 mg/m2 given on days 1, 22, and 43.2 The same treatments were compared in RTOG 9501, which enrolled a total of 459 patients.3,4 However, these 2 studies had different enrollment criteria, defining high-risk disease differently (Table 1). As a result, they unfortunately came to different conclusions regarding the benefit of adjuvant chemoradiation. Based on analysis of these 2 studies, adjuvant chemoradiation seems to improve outcomes in patients with extracapsular extension
Table 1 Adjuvant chemoradiation: comparison between EORTC 22931 and RTOG 9501 EORTC 22931
RTOG 9501
Number of patients
334
459
Oral cavity patients
87
112
Stage
pT3 or pT4/any N or pT1 or pT2/N2 or N3
Any T stage, N2b or higher N stage
Unfavorable pathologic findings
ECE, positive margins, PNI, VTE
2 or more positive nodes, ECE, positive margins
Radiation
54 Gy with boost to 66 Gy
60 Gy with boost to 66 Gy
Chemotherapy
Cisplatin 100 mg/m2 days 1, 22, and 43
Cisplatin 100 mg/m2 days 1, 22, and 43
Findings
Improved 5 y PFS and OS
Improved DFS only for ECE, positive margins
Abbreviations: ECE, extracapsular extension; OS, overall survival; PFS, progression-free survival; PNI, perineural invasion; VTE, vascular tumor embolism. Data from Refs.2–4
Chemotherapy for Oral Cancer
of nodal metastases and in those with positive resection margins. Both studies included a sizable population of patients with oral cancer, approximately 25% to 30% of enrollment in both. Therefore, these findings can be reasonably applied to patients with resected oral cancers. No definitive evidence exists supporting improvement in outcomes for patients with any other high-risk features, including vascular invasion, perineural invasion, T3 and T4 pathologic stage or involvement of 2 or more lymph nodes. Current consensus treatment guidelines recommend that the use of chemoradiation be considered on a case-by-case basis for patients with 1 or more high-risk features other than extracapsular extension of nodal metastases or positive margins.5 For patients who are candidates for combined chemotherapy and radiation, there is no clear consensus on choice of chemotherapy regimen. Both randomized studies addressing this issue used cisplatin 100 mg/m2 on days 1, 22, and 43. However, high-dose cisplatin, although the only regimen supported by randomized phase III clinical trials, is associated with significant risk for acute and late toxicities. Significant risks include kidney failure, hearing loss, tinnitus, nausea, vomiting, and peripheral neuropathy. Furthermore, data clearly indicate that radiation complications (both acute and chronic) are more common in patients treated with chemotherapy. Because of these issues, there has been considerable interest in alternatives to high-dose cisplatin. In the RTOG 9501 trial, only 125 patients (61%) could complete all 3 cycles of cisplatin. Forty-seven patients (23%) only received 2 cycles. In a subset analysis, the 2-year locoregional control rate was 82% in the group that received all planned chemotherapy or had a minor variation in treatment, which was the same as that found for the study as a whole.3 Some have used this as justification for giving only 2 cycles of high-dose cisplatin, although this question has not been studied in a prospective randomized trial. The use of lower dose cisplatin has also been studied with some evidence of benefit compared with radiation alone.6,7 Although no prospective randomized trial has been completed comparing high-dose cisplatin with lower dose weekly cisplatin (typically given at a dose of 30–40 mg/m2) in the adjuvant chemoradiation setting, the currently available evidence suggests that it has similar efficacy and less acute toxicity.8 It is currently a widely used alternative to high-dose cisplatin despite the lack of supporting phase III data. As discussed elsewhere in this article, 1 phase III trial that examined patients being treated with definitive chemoradiation (patients who were not candidates for surgery) found that use of high-dose cisplatin significantly reduced the risk of local recurrence. Based on this and lack of a phase III trial in the adjuvant chemoradiation setting, high-dose cisplatin should be used unless there is a medical contraindication. Cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor, has an established role in the primary treatment of locally advanced unresectable oral cancer when given in combination with radiation, but it has not been studied in the adjuvant setting in combination with radiation. This agent, as well as the chemotherapy agent docetaxel given on a weekly schedule, remain under active investigation, both separately and in combination. However, they are not currently considered standard treatment options for use with adjuvant chemoradiation. PRIMARY CHEMORADIATION
Surgery is often recommended for the initial management of patients with early stage oral squamous cell carcinoma, but many patients present with locally advanced disease that precludes resection. This is a common occurrence in cancers of other
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subsites as well. The use of combined chemotherapy and radiation has been studied extensively for the treatment of locally advanced oral and other head and neck cancers, both as a means of organ preservation and as a primary therapy, even when organ preservation is not necessarily a goal. Notably, although oral cancers were wellrepresented in trials of adjuvant chemoradiation, they have typically been underrepresented in trials of primary chemoradiation. The initial study detailing the benefits of primary concurrent chemoradiation was the VA Larynx trial, although this study used initial chemotherapy followed by combined chemotherapy and radiation in responding patients.9 This study was the first to show that the addition of chemotherapy (cisplatin and 5-fluoracil [5-FU] in this study) to radiation could improve organ preservation. Forastiere and colleagues10 subsequently confirmed the benefit of combined chemotherapy and radiation in larynx cancer. Although this study found no differences in survival between patients treated with induction chemotherapy followed by radiation versus chemoradiation versus radiation alone, it did find a significantly improved organ preservation rate associated with chemoradiation (88% vs 75% for induction chemotherapy and 70% for radiation alone). Along with these trials, multiple other studies have been done, most in patients with either laryngeal or oropharyngeal squamous cell carcinoma. According to the most updated report of the Meta-Analysis of Chemotherapy on Head and Neck Cancer, published in 2009, the use of chemotherapy in addition to definitive local therapy (in this case, radiation) improved survival with an absolute benefit of 6.5% in 5-year survival.1 Notably, no benefit was seen in patients older than 70 years and similar benefit was seen for all subsites, including oral. Also, supporting the usefulness of primary chemoradiation was a single-institution series from the University of Chicago that examined 111 patients, all with oral squamous cell carcinoma, treated at their institution from 1994 to 2008. They found no difference in overall or progression-free survival between patients treated with surgery first and those treated with primary chemoradiation.11 Initial studies of primary chemoradiation used high-dose cisplatin in the same manner that it was used in the adjuvant chemoradiation trials and, as in those studies, toxicity associated with 3 cycles of high-dose cisplatin was significant. Although the efficacy of 2 cycles of high-dose cisplatin versus 3 cycles has not been studied in a prospective manner in the adjuvant setting, it has been examined in one study in the primary treatment setting. In RTOG 0129, chemoradiation with conventional fractionation and 3 cycles of cisplatin 100 mg/m2 was compared with chemoradiation with accelerated boost radiation (42 fractions given over 6 weeks) and only 2 cycles of cisplatin 100 mg/m2.12 This study found no difference in overall survival between these 2 groups, although this does not definitively establish that 2 cycles of cisplatin are equivalent to 3, because 2 variables were changed between the groups. Also, similar to the adjuvant therapy setting, multiple studies have examined use of lower dose weekly cisplatin (typically 30–40 mg/m2).13,14 These studies have found that the use of weekly cisplatin is safe and effective compared with radiotherapy alone. One study has compared high-dose cisplatin with weekly cisplatin given at a dose of 30 mg/m2. This study, which enrolled mostly patients with oral cancer not amenable to surgery, found that use of high-dose cisplatin every 3 weeks was associated with a 42% reduction in the risk of local recurrence.15 Based on these data, high-dose cisplatin is preferred over weekly cisplatin, and weekly cisplatin should be reserved for patients who are not able to be treated with high-dose cisplatin because of medical contraindications. Although it has not been compared directly with high-dose cisplatin, at the present time, lower dose cisplatin is considered an appropriate treatment option based on these data.
Chemotherapy for Oral Cancer
Cetuximab has also been studied in combination with radiation for the primary treatment of locally advanced squamous cell carcinoma of the head and neck. In a pivotal trial, a total of 424 patients with cancers of the larynx, oropharynx, and hypopharynx, treatment with radiation alone was compared with treatment with radiation plus cetuximab.16 In this study, cetuximab was given weekly, with an initial loading dose of 400 mg/m2 1 week before the start of radiotherapy, followed by 250 mg/m2 weekly during radiation treatment. At a median follow-up of 54 months, there was a significant improvement in overall survival observed in the group treated with cetuximab (median of 49.0 months vs 29.3 months). Of note, this study did not include patients with oral cancer, so conclusions cannot be drawn regarding the efficacy of cetuximab combined with radiation for treatment of oral cancer at this time. Also of importance, patients older than 65 years and those with poorer performance status did not clearly benefit. Based on the data summarized, it is most reasonable to conclude that primary chemoradiation has a definite role in the management of unresectable oral squamous cell carcinoma. Compared with radiation alone, it improves survival and reduces the risk of recurrence. However, it does not seem to benefit patients older than 70 years. Use of high-dose cisplatin is preferred for fit patients. For patients not appropriate for highdose cisplatin, lower dose weekly regimens are recommended. Cetuximab, although used in this setting, is not supported by any data in patients with oral cancer and cannot be recommended routinely. INDUCTION CHEMOTHERAPY
Induction chemotherapy refers to initial chemotherapy treatment before definitive local therapy. This treatment typically is combination chemotherapy, and the use of such treatment has some putative advantages. These advantages include potentially reducing the risk of metastatic recurrence and downsizing of the primary tumor to improve locoregional control. One of the first uses of induction chemotherapy was in the VA Larynx trial.9 In that study, patients were treated with 2 cycles of full-dose cisplatin and 5-FU before going on to treatment with definitive local therapy based on response. More recent studies have combined induction chemotherapy with primary chemoradiation, in an effort to both improve locoregional control and decrease metastatic recurrence. Those studies have also studied the addition of other agents to cisplatin and 5-FU, most importantly docetaxel. For example, in the TAX 324 trial (A Randomized Phase III Multicenter Trial of Neoadjuvant Docetaxel (Taxotere) Plus Cisplatin Plus 5-Fluorouracil Versus Neoadjuvant Cisplatin Plus 5-Fluorouracil in Patients With Locally Advanced Inoperable Squamous Cell Carcinoma of the Head and Neck), induction treatment with cisplatin and 5-FU was compared with TPF (docetaxel 75 mg/m2, cisplatin 100 mg/m2, and 5-FU 1000 mg/m2 continuous infusion on days 1–5).17 This study enrolled 501 patients, and after 3 cycles of induction chemotherapy, all patients were treated with radiation combined with carboplatin. At a median follow-up of 72 months, the TPF regimen was associated with an improvement in overall survival as well as progression-free survival. In EORTC 24971/TAX 323, a slightly different TPF regimen (cisplatin 75 mg/m2 and 5-FU 750 mg/m2 continuous infused on days 1–4) was used, and in this study, TPF also improved progressionfree survival and overall survival.18 This study did not use chemoradiation after induction therapy. Rather, patients were treated with radiation alone. Both studies included patients with oral cancers, about 13% to 17% of the study population. Although those 2 regimens have not been compared directly, either is an acceptable induction chemotherapy regimen. Notably, use of high-dose cisplatin combined with radiation
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after treatment with full-dose induction chemotherapy is not recommended owing to significant safety concerns. The improvement in survival observed with the addition of docetaxel to cisplatin and 5-FU induction chemotherapy raised important questions regarding the optimal use of TPF induction chemotherapy. Although it had been shown to improve survival compared with cisplatin and 5-FU, it was also associated with a significant increase in toxicity, including some treatment-related deaths. In addition, it remained unclear whether the combination of TPF with chemoradiation could improve outcomes compared with use of chemoradiation alone. Multiple studies have since been initiated to answer this important question. In the DeCIDE trial (A phase III randomized trial of docetaxel, cisplatin, 5-fluorouracil, (TPF) induction chemotherapy in patients with N2/ N3 locally advanced squamous cell carcinoma of the head and neck), 280 patients with N2 or N3 disease were treated with either upfront chemoradiation or 2 cycles of TPF followed by chemoradiation using docetaxel, 5-FU, and hydroxyurea.19 This study enrolled only 280 and, thus far, has found no significant difference in outcome between these 2 groups. Also relevant is a phase II/III trial centered in Italy that enrolled 421 patients and which has only been reported in abstract form.20 Treatment in this study was 3 cycles of TPF induction chemotherapy followed by chemoradiation compared with treatment with chemoradiation alone. This study also included a second randomization between PF (cisplatin, 5-FU) and cetuximab-based chemoradiation. At a median follow-up of 41 months, treatment with induction chemotherapy significantly improved overall survival compared with concurrent chemoradiation alone. Median survival was 54 versus 30 months, with 3-year survival rates of 58% versus 46%. At the present time, therefore, the use of induction chemotherapy with TPF followed by chemoradiation remains of unclear benefit compared with chemoradiation alone. Studies have shown that, although it is superior to PF-based induction chemotherapy, it is not definitely superior to treatment with modern chemoradiation without induction. Also, as noted, it is associated with a significant incidence of both hematologic and nonhematologic toxicity. Therefore, although induction chemotherapy can be considered in selected patients, it is not yet a routine standard treatment option. The actual efficacy in oral cancers also remains somewhat poorly defined. Although patients with oral cancer were represented in the TPF versus PF trials and were also included in the DeCIDE trial at a rate similar to those studies, the degree of their representation in the Italian trial is not known. Further study is needed to define more clearly the role of induction chemotherapy in patients with locally advanced oral cancers. METASTATIC DISEASE
The treatment of metastatic oral squamous cell carcinoma has changed significantly over the past several years. Although metastatic disease is an uncommon occurrence in patients, classically, treatment options have been limited and responses not common. However, recent studies have identified new agents that have been shown to improve survival outcomes in the metastatic disease setting. Treatment of patients with metastatic disease is palliative and the median survival of patients with metastatic oral cancer mirrors that of patients with head and neck cancer in general, which is approximately 6 to 12 months.21 Standard chemotherapy for front-line treatment of metastatic disease has typically been with cisplatin or carboplatin containing regimens. These drugs have activity as single agents, but in the front-line setting, they are most commonly used in combination with other chemotherapy agents, such as 5-FU, docetaxel, and paclitaxel. At the
Chemotherapy for Oral Cancer
present time, there is no convincing evidence supporting any efficacy difference between these 2 agents, although there are clear differences in side effects. Carboplatin is associated more commonly with myelosuppression than cisplatin and avoids the more significant cisplatin-related complications of neuropathy, hearing toxicity, and acute kidney injury. For these reasons, carboplatin is often used in the treatment of patients with metastatic disease. To date, there is no convincing evidence that use of a platinum-based combination chemotherapy regimen improves survival compared with use of single-agent chemotherapy, although the evidence does indicate that response rate is higher with combination therapy. For example, cisplatin with 5-FU has been found to have a response rate of about 30%, which is higher than cisplatin alone and about the same as cisplatin and paclitaxel.22,23 In a study comparing cisplatin and 5-FU with cisplatin and paclitaxel, response rates were the same (27% vs 26%) and median overall survival was also the same (8.7 months vs 8.1 months).22 In an older study that compared cisplatin, 5-FU, and the combination, there was again no difference in overall survival between these 3 groups at about 5.7 months for all three.23 Non–platinum-based chemotherapy has been studied in a limited fashion and has not been compared directly with platinum-based chemotherapy. For example, the combination of gemcitabine (3000 mg/m2) and paclitaxel (150 mg/m2) given every 14 days was studied in an Southwest Oncology Group phase II trial and found to have a response rate of 28% with an overall survival of about 8 months.24 Whether these results are superior to those with single agent paclitaxel remains unanswered. Also, the combination of paclitaxel and cetuximab given weekly was found to have a response rate of 54% and an overall survival of 8.1 months.25 For patients unable to tolerate platinum-based treatment, these are reasonable options. In addition to its role as a radiation sensitizer for patients with locally advanced disease, cetuximab has been studied in the treatment of metastatic disease. Early studies with this agent were done for the treatment of recurrent metastatic disease and, in those studies, it was used as a single agent with evidence of modest activity as discussed elsewhere in this article. To improve treatment outcomes in the firstline treatment setting, studies were done combining cetuximab with platinum-based combination chemotherapy regimens in previously untreated patients. In the phase III EXTREME trial (Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer), 442 patients with recurrent or metastatic head and neck cancer were treated with platinum (either cisplatin or carboplatin) plus 5-FU with or without cetuximab.26 Patients with oral cancer were well-represented in this study, accounting for about 20% of the treatment population. In this study, chemotherapy was given for a maximum of 6 cycles, after which cetuximab could be continued as a single agent. This study found that the addition of cetuximab resulted in a significant improvement in overall survival, increased from 7.4 months to 10.1 months. Both progression-free survival and response rate were also increased. This improvement came without a significant increase in severe toxicity, and based on this data, cetuximab has been approved by the US Food and Drug Administration for use in the front-line treatment setting in combination with platinum and 5-FU–based chemotherapy. Panitumumab, a fully human monoclonal antibody also directed against the epidermal growth factor receptor, has been studied in the treatment of metastatic head and neck cancers. Currently, however, this agent does not have an established role in the treatment of head and neck cancer and has not been shown to improve survival when given with front-line cisplatin plus 5-FU chemotherapy.27 For patients with progression after front-line chemotherapy, multiple options exist. These include cytotoxic chemotherapy, programmed cell death (PD)-1 inhibitors,
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cetuximab, and small molecule tyrosine kinase inhibitors. Choice of treatment depends on prior treatment history, performance status, and the presence or absence of significant medical comorbid illnesses. There has been considerable excitement surrounding use of PD-1 inhibitors, which have been found recently to improve survival in this treatment setting. PD-1 is a receptor expressed on T cells, B cells, and natural killer cells. It functions, along with PD-ligand 1 (PD-L1) and PD-L2, to suppress immune function by downregulating the activity of effector T cells. PD-L1 and PD-L2 are expressed on many different cell types throughout the body and they are also expressed commonly on tumor cells. By taking advantage of this receptor–ligand complex, tumor cells can evade destruction by effector T cells. Many different monoclonal antibodies have been developed for the purpose of interfering with the PD-1/PD-L1 axis. These agents do not cause side effects commonly associated with chemotherapy, such as myelosuppression, nausea, vomiting, and fatigue. However, they can cause a variety of autoimmune toxicities, and although they are often well-tolerated as single agents, toxicity can occur suddenly and be severe, even potentially fatal, if not recognized and treated promptly. Common side effects include rash, diarrhea, hepatitis, thyroiditis, hypophysitis, and pneumonitis. Approved agents to date include nivolumab, pembrolizumab, and atezolizumab. Both nivolumab and pembrolizumab have shown activity in the treatment of recurrent and metastatic head and neck cancers and both are currently FDA approved for the treatment of metastatic head and neck cancer with progression after first-line platinum-containing chemotherapy. Nivolumab was studied in a phase III clinical trial that enrolled patients with platinum-refractory recurrent or metastatic disease. Notably, about one-half of the enrolled patients had metastatic oral cancers. It was compared with investigator’s choice of single-agent therapy, with options including cetuximab, methotrexate, and docetaxel.28 In this study, a total of 361 patients were treated and nivolumab improved overall survival from 5.1 months to 7.5 months. PD-L1 expression was measured in all patients, and it was found that, in patients with expression of 1% or higher, survival was improved with the use of nivolumab. The FDA approval of nivolumab does not require measurement of PD-L1 expression. It is given at a dose of 3 mg/kg intravenously every 2 weeks. Pembrolizumab, in contrast, was approved provisionally in August 2016 based on the results of a phase Ib clinical trial.29 This study enrolled 174 patients with progression on or after platinum-based chemotherapy. Initial results were notable for a 16% response rate, notably including 8 complete responses (5% of the population). Also, most responses (23 of 28) lasted longer than 6 months. Updated results presented in 2016 at the American Society of Clinical Oncology meeting were notable for median overall survival of 8 months and 12-month survival of 38%.30 This agent is currently FDA approved at a fixed dose of 200 mg given intravenously every 3 weeks, and also does not require measurement of tumor PD-L1 expression. Two phase III trials are ongoing to confirm these results. In addition to these monoclonal antibodies, cetuximab has modest activity in the treatment of recurrent or metastatic head and neck cancers. For example, in 1 series of 103 patients who had progression after previous treatment with platinum-based chemotherapy, it was associated with a response rate of 13% and a median survival of 7.5 months.31 Multiple small molecule tyrosine kinase inhibitors have been studied in the treatment of advanced head and neck cancer. These include gefitnib,32,33 afatinib,34 sunitinib,35 and erlotinib.36 To date, however, no study has found evidence of convincing activity or improvement in overall survival associated with these agents.
Chemotherapy for Oral Cancer
Various cytotoxic chemotherapy drugs have been studied in the second-line setting and beyond. Overall, studies have failed to document significant benefit and, to date, there is no study that has found evidence of improved survival associated with cytotoxic chemotherapy in the second-line setting or beyond. Agents that have been studied include methotrexate,33 gemcitabine,37 paclitaxel,38 docetaxel,39 and 5-FU.23 Choice of agent depends on prior treatment history and differences in expected toxicity between the agents, because there are no comparative studies to guide decision making. Given the limited available treatment options for patients with metastatic disease, particularly after second-line treatment with PD-1 inhibitor–based therapy, it is important to closely monitor symptoms and to discuss prognosis and goals of care. Recurrent and metastatic head and neck cancer carries the potential for considerable morbidity combined with short survival, and a transition away from active treatment and toward comfort care and hospice should be pursued when appropriate. REFERENCES
1. Pignon JP, le Maitre A, Maillard E, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92:4–14. 2. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945–52. 3. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937–44. 4. Cooper JS, Zhang Q, Pajak TF, et al. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2012;84:1198–205. 5. Head and Neck Cancers. Version 1.2017. 2017. NCCN Guidelines. Available at: https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. Accessed April 12, 2017. 6. Bachaud JM, Cohen-Jonathan E, Alzieu C, et al. Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma: final report of a randomized trial. Int J Radiat Oncol Biol Phys 1996;36: 999–1004. 7. Franchin G, Minatel E, Politi D, et al. Postoperative reduced dose of cisplatin concomitant with radiation therapy in high- risk head and neck squamous cell carcinoma. Cancer 2009;115:2464–71. 8. Melotek JM, Cooper BT, Koshy M, et al. Weekly versus every-three weeks platinum-based chemoradiation regimens for head and neck cancer. J Otolaryngol Head Neck Surg 2016;45:62–70. 9. The Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 1991;324:1685–90. 10. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349:2091–8. 11. Stenson KM, Kunnavakkam R, Cohen EE, et al. Chemoradiation for patients with advanced oral cavity cancer. Laryngoscope 2010;120:93–9.
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12. Nguyen-Tan PF, Zhang Q, Ang KK, et al. Randomized phase III trial to test accelerated versus standard fractionation in combination with concurrent cisplatin for head and neck carcinomas in the Radiation Therapy Oncology Group 0129 trial: long-term report of efficacy and toxicity. J Clin Oncol 2014;32:3858–66. 13. Sharma A, Mohanti BK, Thakar A, et al. Concomitant chemoradiation versus radical radiotherapy in advanced squamous cell carcinoma of oropharynx and nasopharynx using weekly cisplatin: a phase II randomized trial. Ann Oncol 2010;21:2272–7. 14. Traynor AM, Richards GM, Hartig GK, et al. Comprehensive IMRT plus weekly cisplatin for advanced head and neck cancer: the University of Wisconsin experience. Head Neck 2010;32:599–606. 15. Noronha V, Joshi A, Patil VM, et al. Phase III randomized trial comparing weekly versus three-weekly (W3W) cisplatin in patients receiving chemoradiation for locally advanced head and neck cancer. J Clin Oncol 2017;35(Suppl 15); abstr 6007. 16. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamouscell carcinoma of the head and neck. N Engl J Med 2006;354:567–78. 17. Lorch JH, Goloubeva O, Haddad RI, et al. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol 2011;12:153–9. 18. Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357:1695–704. 19. Cohen EE, Karrison TG, Kocherginsky M, et al. Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. J Clin Oncol 2014;32:2735–43. 20. Ghi MG, Paccagnella A, Ferrari D, et al. Concomitant chemoradiation (CRT) or cetuximab/RT (CET/RT) versus induction Docetaxel/Cisplatin/5-Fluorouracil (TPF) followed by CRT or CET/RT in patients with Locally Advanced Squamous Cell Carcinoma of Head and Neck (LASCCHN). A randomized phase III factorial study (NCT01086826). J Clin Oncol 2014;32(Suppl 15); abstr 6004. 21. Shah D, Hoffman GR. Outcome of head and neck cancer patients who did not receive curative-intent treatment. J Oral Maxillofac Surg 2017. [Epub ahead of print]. 22. Gibson MK, Li Y, Murphy B, et al. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an Intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2005;23:3562–7. 23. Jacobs C, Lyman G, Velez-Garcia E, et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 1992; 10:257–63. 24. Malhotra B, Moon J, Kucuk O, et al. Phase II trial of biweekly gemcitabine and paclitaxel with recurrent or metastatic squamous cell carcinoma of the head and neck. Southwest Oncology Group study S0329. Head Neck 2014;36:1712–7. 25. Hitt R, Irigoyen A, Cortes-Funes H, et al. Phase II study of the combination of cetuximab and weekly paclitaxel in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of head and neck. Ann Oncol 2012; 23:1016–22. 26. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359:1116–27.
Chemotherapy for Oral Cancer
27. Vermorken JB, Stohlmacher-Williams J, Davidenko I, et al. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncol 2013;14:697–710. 28. Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for recurrent squamouscell carcinoma of the head and neck. N Engl J Med 2016;375:1856–67. 29. US Food and Drug Administration (FDA). DA approval statement for pembrolizumab (Keytruda). Available at: https://www.fda.gov/drugs/informationondrugs/ approveddrugs/ucm515627.htm. Accessed April 13, 2017. 30. Mehra R, Seiwert TY, Mahipal A, et al. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC): pooled analyses after long-term follow-up in KEYNOTE-012. J Clin Oncol 2016; 34(Suppl 15); abstr 6012. 31. Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 2007;25: 2171–7. 32. Cohen EE, Kane MA, List MA, et al. Phase II trial of gefitinib 250mg daily in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res 2005;11:8418–24. 33. Stewart JS, Cohen EE, Licitra L, et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J Clin Oncol 2009;27:1864–71. 34. Machiels JP, Haddad RI, Fayette J, et al. Afatinib versus methotrexate as secondline treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head&Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol 2015;16:583–94. 35. Machiels JP, Henry S, Zanetta S, et al. Phase II study of sunitinib in recurrent or metastatic squamous cell carcinoma of the head and neck: GORTEC 2006-01. J Clin Oncol 2010;28:21–8. 36. Soulieres D, Senzer NN, Vokes EE, et al. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2004;22:77–85. 37. Catimel G, Vermorken JB, Clavel M, et al. A phase II study of Gemcitabine (LY 188011) in patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group. Ann Oncol 1994;5:543–7. 38. Grau JJ, Caballero M, Verger E, et al. Weekly paclitaxel for platin-resistant stage IV head and neck cancer patients. Acta Otolaryngol 2009;129:1294–9. 39. Guardiola E, Peyrade F, Chaigneau L, et al. Results of a randomised phase II study comparing docetaxel with methotrexate in patients with recurrent head and neck cancer. Eur J Cancer 2004;40:2071–6.
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KEYWORDS Chemotherapy Oral cancer Chemoradiation Cisplatin Cetuximab Nivolumab Pembrolizumab KEY POINTS Adjuvant chemotherapy has not been shown to improve treatment outcomes in patients with oral cancer after surgery and should not be used. Adjuvant combined chemotherapy and radiation improves survival for patients with extracapsular extension in nodal metastases and positive resection margins. Cisplatin should be used. Patients with oral cancer can be treated with primary chemoradiation, although the impact on survival is unclear. Cisplatin is the standard agent to combine with radiation. Cetuximab has not been well-studied. Induction chemotherapy can be used selectively, but its impact on overall survival remains unclear and is associated with significant toxicity. Anti– programmed cell death-ligand 1 antibodies have been shown to improve survival for patients with metastatic disease after treatment with platinum-based chemotherapy.
INTRODUCTION
The past several years have seen major advances in the use of systemic therapy for treatment of patients with oral cancer. Systemic therapy refers to chemotherapy and immunotherapy drugs, which are playing an increasingly important role in treatment. Chemotherapy has classically been used either as a primary treatment modality or in combination with radiation, where it is used as a radiation sensitizer. Based on the results of pivotal trials during the past decade, the use of systemic therapy has expanded in scope and has resulted in meaningful improvements in patient outcomes. This article discusses the different uses for systemic therapy in the treatment of patients with oral squamous cell carcinoma and reviews the current state of practice and areas of future investigation. In discussing studies, the relevance to patients with oral cancer are highlighted. It is important to remember that studies in patients
Conflicts of Interest: None to report. Abramson Cancer Center at Pennsylvania Hospital, 230 West Washington Square, Philadelphia, PA 19106, USA E-mail address: [email protected] Dent Clin N Am - (2017) -–http://dx.doi.org/10.1016/j.cden.2017.08.006 0011-8532/17/ª 2017 Elsevier Inc. All rights reserved.
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with squamous cell carcinoma of the head and neck include patients with different primary sites and they are not always represented in the same relative amounts. Despite that, however, the results of these studies are in most cases applied to patients with primary tumors of all different subsites. ADJUVANT CHEMOTHERAPY
The primary treatment modality for patients with oral cancer is surgery when possible without undue morbidity. Adjuvant chemotherapy is given after surgery in many types of cancer for reducing the incidence of metastatic recurrence. At the present time, adjuvant chemotherapy has no established role in the treatment of patients after surgery for oral cancer. The most recent update of a very large metaanalysis examining the role of chemotherapy in treatment of patients with head and neck cancer found no evidence of benefit.1 It included a total of 2567 patients taken from 6 studies that included patients with oral cancer. Therefore, adjuvant chemotherapy should only be used in the context of a clinical trial. ADJUVANT CHEMORADIOTHERAPY
In addition to studies of chemotherapy as a standalone adjuvant treatment modality, multiple studies have examined the use of concurrent chemotherapy and radiation. In this setting, chemotherapy is given as a radiation sensitizer with the goal of reducing radiation resistance. Multiple studies have found this approach is superior to radiation alone in patients with an increased risk of recurrence. The 2 largest trials examining this question, unfortunately, came to different conclusions. In the EORTC trial 22,931, a total of 334 patients were treated with either radiation alone or radiation combined with cisplatin 100 mg/m2 given on days 1, 22, and 43.2 The same treatments were compared in RTOG 9501, which enrolled a total of 459 patients.3,4 However, these 2 studies had different enrollment criteria, defining high-risk disease differently (Table 1). As a result, they unfortunately came to different conclusions regarding the benefit of adjuvant chemoradiation. Based on analysis of these 2 studies, adjuvant chemoradiation seems to improve outcomes in patients with extracapsular extension
Table 1 Adjuvant chemoradiation: comparison between EORTC 22931 and RTOG 9501 EORTC 22931
RTOG 9501
Number of patients
334
459
Oral cavity patients
87
112
Stage
pT3 or pT4/any N or pT1 or pT2/N2 or N3
Any T stage, N2b or higher N stage
Unfavorable pathologic findings
ECE, positive margins, PNI, VTE
2 or more positive nodes, ECE, positive margins
Radiation
54 Gy with boost to 66 Gy
60 Gy with boost to 66 Gy
Chemotherapy
Cisplatin 100 mg/m2 days 1, 22, and 43
Cisplatin 100 mg/m2 days 1, 22, and 43
Findings
Improved 5 y PFS and OS
Improved DFS only for ECE, positive margins
Abbreviations: ECE, extracapsular extension; OS, overall survival; PFS, progression-free survival; PNI, perineural invasion; VTE, vascular tumor embolism. Data from Refs.2–4
Chemotherapy for Oral Cancer
of nodal metastases and in those with positive resection margins. Both studies included a sizable population of patients with oral cancer, approximately 25% to 30% of enrollment in both. Therefore, these findings can be reasonably applied to patients with resected oral cancers. No definitive evidence exists supporting improvement in outcomes for patients with any other high-risk features, including vascular invasion, perineural invasion, T3 and T4 pathologic stage or involvement of 2 or more lymph nodes. Current consensus treatment guidelines recommend that the use of chemoradiation be considered on a case-by-case basis for patients with 1 or more high-risk features other than extracapsular extension of nodal metastases or positive margins.5 For patients who are candidates for combined chemotherapy and radiation, there is no clear consensus on choice of chemotherapy regimen. Both randomized studies addressing this issue used cisplatin 100 mg/m2 on days 1, 22, and 43. However, high-dose cisplatin, although the only regimen supported by randomized phase III clinical trials, is associated with significant risk for acute and late toxicities. Significant risks include kidney failure, hearing loss, tinnitus, nausea, vomiting, and peripheral neuropathy. Furthermore, data clearly indicate that radiation complications (both acute and chronic) are more common in patients treated with chemotherapy. Because of these issues, there has been considerable interest in alternatives to high-dose cisplatin. In the RTOG 9501 trial, only 125 patients (61%) could complete all 3 cycles of cisplatin. Forty-seven patients (23%) only received 2 cycles. In a subset analysis, the 2-year locoregional control rate was 82% in the group that received all planned chemotherapy or had a minor variation in treatment, which was the same as that found for the study as a whole.3 Some have used this as justification for giving only 2 cycles of high-dose cisplatin, although this question has not been studied in a prospective randomized trial. The use of lower dose cisplatin has also been studied with some evidence of benefit compared with radiation alone.6,7 Although no prospective randomized trial has been completed comparing high-dose cisplatin with lower dose weekly cisplatin (typically given at a dose of 30–40 mg/m2) in the adjuvant chemoradiation setting, the currently available evidence suggests that it has similar efficacy and less acute toxicity.8 It is currently a widely used alternative to high-dose cisplatin despite the lack of supporting phase III data. As discussed elsewhere in this article, 1 phase III trial that examined patients being treated with definitive chemoradiation (patients who were not candidates for surgery) found that use of high-dose cisplatin significantly reduced the risk of local recurrence. Based on this and lack of a phase III trial in the adjuvant chemoradiation setting, high-dose cisplatin should be used unless there is a medical contraindication. Cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor, has an established role in the primary treatment of locally advanced unresectable oral cancer when given in combination with radiation, but it has not been studied in the adjuvant setting in combination with radiation. This agent, as well as the chemotherapy agent docetaxel given on a weekly schedule, remain under active investigation, both separately and in combination. However, they are not currently considered standard treatment options for use with adjuvant chemoradiation. PRIMARY CHEMORADIATION
Surgery is often recommended for the initial management of patients with early stage oral squamous cell carcinoma, but many patients present with locally advanced disease that precludes resection. This is a common occurrence in cancers of other
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subsites as well. The use of combined chemotherapy and radiation has been studied extensively for the treatment of locally advanced oral and other head and neck cancers, both as a means of organ preservation and as a primary therapy, even when organ preservation is not necessarily a goal. Notably, although oral cancers were wellrepresented in trials of adjuvant chemoradiation, they have typically been underrepresented in trials of primary chemoradiation. The initial study detailing the benefits of primary concurrent chemoradiation was the VA Larynx trial, although this study used initial chemotherapy followed by combined chemotherapy and radiation in responding patients.9 This study was the first to show that the addition of chemotherapy (cisplatin and 5-fluoracil [5-FU] in this study) to radiation could improve organ preservation. Forastiere and colleagues10 subsequently confirmed the benefit of combined chemotherapy and radiation in larynx cancer. Although this study found no differences in survival between patients treated with induction chemotherapy followed by radiation versus chemoradiation versus radiation alone, it did find a significantly improved organ preservation rate associated with chemoradiation (88% vs 75% for induction chemotherapy and 70% for radiation alone). Along with these trials, multiple other studies have been done, most in patients with either laryngeal or oropharyngeal squamous cell carcinoma. According to the most updated report of the Meta-Analysis of Chemotherapy on Head and Neck Cancer, published in 2009, the use of chemotherapy in addition to definitive local therapy (in this case, radiation) improved survival with an absolute benefit of 6.5% in 5-year survival.1 Notably, no benefit was seen in patients older than 70 years and similar benefit was seen for all subsites, including oral. Also, supporting the usefulness of primary chemoradiation was a single-institution series from the University of Chicago that examined 111 patients, all with oral squamous cell carcinoma, treated at their institution from 1994 to 2008. They found no difference in overall or progression-free survival between patients treated with surgery first and those treated with primary chemoradiation.11 Initial studies of primary chemoradiation used high-dose cisplatin in the same manner that it was used in the adjuvant chemoradiation trials and, as in those studies, toxicity associated with 3 cycles of high-dose cisplatin was significant. Although the efficacy of 2 cycles of high-dose cisplatin versus 3 cycles has not been studied in a prospective manner in the adjuvant setting, it has been examined in one study in the primary treatment setting. In RTOG 0129, chemoradiation with conventional fractionation and 3 cycles of cisplatin 100 mg/m2 was compared with chemoradiation with accelerated boost radiation (42 fractions given over 6 weeks) and only 2 cycles of cisplatin 100 mg/m2.12 This study found no difference in overall survival between these 2 groups, although this does not definitively establish that 2 cycles of cisplatin are equivalent to 3, because 2 variables were changed between the groups. Also, similar to the adjuvant therapy setting, multiple studies have examined use of lower dose weekly cisplatin (typically 30–40 mg/m2).13,14 These studies have found that the use of weekly cisplatin is safe and effective compared with radiotherapy alone. One study has compared high-dose cisplatin with weekly cisplatin given at a dose of 30 mg/m2. This study, which enrolled mostly patients with oral cancer not amenable to surgery, found that use of high-dose cisplatin every 3 weeks was associated with a 42% reduction in the risk of local recurrence.15 Based on these data, high-dose cisplatin is preferred over weekly cisplatin, and weekly cisplatin should be reserved for patients who are not able to be treated with high-dose cisplatin because of medical contraindications. Although it has not been compared directly with high-dose cisplatin, at the present time, lower dose cisplatin is considered an appropriate treatment option based on these data.
Chemotherapy for Oral Cancer
Cetuximab has also been studied in combination with radiation for the primary treatment of locally advanced squamous cell carcinoma of the head and neck. In a pivotal trial, a total of 424 patients with cancers of the larynx, oropharynx, and hypopharynx, treatment with radiation alone was compared with treatment with radiation plus cetuximab.16 In this study, cetuximab was given weekly, with an initial loading dose of 400 mg/m2 1 week before the start of radiotherapy, followed by 250 mg/m2 weekly during radiation treatment. At a median follow-up of 54 months, there was a significant improvement in overall survival observed in the group treated with cetuximab (median of 49.0 months vs 29.3 months). Of note, this study did not include patients with oral cancer, so conclusions cannot be drawn regarding the efficacy of cetuximab combined with radiation for treatment of oral cancer at this time. Also of importance, patients older than 65 years and those with poorer performance status did not clearly benefit. Based on the data summarized, it is most reasonable to conclude that primary chemoradiation has a definite role in the management of unresectable oral squamous cell carcinoma. Compared with radiation alone, it improves survival and reduces the risk of recurrence. However, it does not seem to benefit patients older than 70 years. Use of high-dose cisplatin is preferred for fit patients. For patients not appropriate for highdose cisplatin, lower dose weekly regimens are recommended. Cetuximab, although used in this setting, is not supported by any data in patients with oral cancer and cannot be recommended routinely. INDUCTION CHEMOTHERAPY
Induction chemotherapy refers to initial chemotherapy treatment before definitive local therapy. This treatment typically is combination chemotherapy, and the use of such treatment has some putative advantages. These advantages include potentially reducing the risk of metastatic recurrence and downsizing of the primary tumor to improve locoregional control. One of the first uses of induction chemotherapy was in the VA Larynx trial.9 In that study, patients were treated with 2 cycles of full-dose cisplatin and 5-FU before going on to treatment with definitive local therapy based on response. More recent studies have combined induction chemotherapy with primary chemoradiation, in an effort to both improve locoregional control and decrease metastatic recurrence. Those studies have also studied the addition of other agents to cisplatin and 5-FU, most importantly docetaxel. For example, in the TAX 324 trial (A Randomized Phase III Multicenter Trial of Neoadjuvant Docetaxel (Taxotere) Plus Cisplatin Plus 5-Fluorouracil Versus Neoadjuvant Cisplatin Plus 5-Fluorouracil in Patients With Locally Advanced Inoperable Squamous Cell Carcinoma of the Head and Neck), induction treatment with cisplatin and 5-FU was compared with TPF (docetaxel 75 mg/m2, cisplatin 100 mg/m2, and 5-FU 1000 mg/m2 continuous infusion on days 1–5).17 This study enrolled 501 patients, and after 3 cycles of induction chemotherapy, all patients were treated with radiation combined with carboplatin. At a median follow-up of 72 months, the TPF regimen was associated with an improvement in overall survival as well as progression-free survival. In EORTC 24971/TAX 323, a slightly different TPF regimen (cisplatin 75 mg/m2 and 5-FU 750 mg/m2 continuous infused on days 1–4) was used, and in this study, TPF also improved progressionfree survival and overall survival.18 This study did not use chemoradiation after induction therapy. Rather, patients were treated with radiation alone. Both studies included patients with oral cancers, about 13% to 17% of the study population. Although those 2 regimens have not been compared directly, either is an acceptable induction chemotherapy regimen. Notably, use of high-dose cisplatin combined with radiation
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after treatment with full-dose induction chemotherapy is not recommended owing to significant safety concerns. The improvement in survival observed with the addition of docetaxel to cisplatin and 5-FU induction chemotherapy raised important questions regarding the optimal use of TPF induction chemotherapy. Although it had been shown to improve survival compared with cisplatin and 5-FU, it was also associated with a significant increase in toxicity, including some treatment-related deaths. In addition, it remained unclear whether the combination of TPF with chemoradiation could improve outcomes compared with use of chemoradiation alone. Multiple studies have since been initiated to answer this important question. In the DeCIDE trial (A phase III randomized trial of docetaxel, cisplatin, 5-fluorouracil, (TPF) induction chemotherapy in patients with N2/ N3 locally advanced squamous cell carcinoma of the head and neck), 280 patients with N2 or N3 disease were treated with either upfront chemoradiation or 2 cycles of TPF followed by chemoradiation using docetaxel, 5-FU, and hydroxyurea.19 This study enrolled only 280 and, thus far, has found no significant difference in outcome between these 2 groups. Also relevant is a phase II/III trial centered in Italy that enrolled 421 patients and which has only been reported in abstract form.20 Treatment in this study was 3 cycles of TPF induction chemotherapy followed by chemoradiation compared with treatment with chemoradiation alone. This study also included a second randomization between PF (cisplatin, 5-FU) and cetuximab-based chemoradiation. At a median follow-up of 41 months, treatment with induction chemotherapy significantly improved overall survival compared with concurrent chemoradiation alone. Median survival was 54 versus 30 months, with 3-year survival rates of 58% versus 46%. At the present time, therefore, the use of induction chemotherapy with TPF followed by chemoradiation remains of unclear benefit compared with chemoradiation alone. Studies have shown that, although it is superior to PF-based induction chemotherapy, it is not definitely superior to treatment with modern chemoradiation without induction. Also, as noted, it is associated with a significant incidence of both hematologic and nonhematologic toxicity. Therefore, although induction chemotherapy can be considered in selected patients, it is not yet a routine standard treatment option. The actual efficacy in oral cancers also remains somewhat poorly defined. Although patients with oral cancer were represented in the TPF versus PF trials and were also included in the DeCIDE trial at a rate similar to those studies, the degree of their representation in the Italian trial is not known. Further study is needed to define more clearly the role of induction chemotherapy in patients with locally advanced oral cancers. METASTATIC DISEASE
The treatment of metastatic oral squamous cell carcinoma has changed significantly over the past several years. Although metastatic disease is an uncommon occurrence in patients, classically, treatment options have been limited and responses not common. However, recent studies have identified new agents that have been shown to improve survival outcomes in the metastatic disease setting. Treatment of patients with metastatic disease is palliative and the median survival of patients with metastatic oral cancer mirrors that of patients with head and neck cancer in general, which is approximately 6 to 12 months.21 Standard chemotherapy for front-line treatment of metastatic disease has typically been with cisplatin or carboplatin containing regimens. These drugs have activity as single agents, but in the front-line setting, they are most commonly used in combination with other chemotherapy agents, such as 5-FU, docetaxel, and paclitaxel. At the
Chemotherapy for Oral Cancer
present time, there is no convincing evidence supporting any efficacy difference between these 2 agents, although there are clear differences in side effects. Carboplatin is associated more commonly with myelosuppression than cisplatin and avoids the more significant cisplatin-related complications of neuropathy, hearing toxicity, and acute kidney injury. For these reasons, carboplatin is often used in the treatment of patients with metastatic disease. To date, there is no convincing evidence that use of a platinum-based combination chemotherapy regimen improves survival compared with use of single-agent chemotherapy, although the evidence does indicate that response rate is higher with combination therapy. For example, cisplatin with 5-FU has been found to have a response rate of about 30%, which is higher than cisplatin alone and about the same as cisplatin and paclitaxel.22,23 In a study comparing cisplatin and 5-FU with cisplatin and paclitaxel, response rates were the same (27% vs 26%) and median overall survival was also the same (8.7 months vs 8.1 months).22 In an older study that compared cisplatin, 5-FU, and the combination, there was again no difference in overall survival between these 3 groups at about 5.7 months for all three.23 Non–platinum-based chemotherapy has been studied in a limited fashion and has not been compared directly with platinum-based chemotherapy. For example, the combination of gemcitabine (3000 mg/m2) and paclitaxel (150 mg/m2) given every 14 days was studied in an Southwest Oncology Group phase II trial and found to have a response rate of 28% with an overall survival of about 8 months.24 Whether these results are superior to those with single agent paclitaxel remains unanswered. Also, the combination of paclitaxel and cetuximab given weekly was found to have a response rate of 54% and an overall survival of 8.1 months.25 For patients unable to tolerate platinum-based treatment, these are reasonable options. In addition to its role as a radiation sensitizer for patients with locally advanced disease, cetuximab has been studied in the treatment of metastatic disease. Early studies with this agent were done for the treatment of recurrent metastatic disease and, in those studies, it was used as a single agent with evidence of modest activity as discussed elsewhere in this article. To improve treatment outcomes in the firstline treatment setting, studies were done combining cetuximab with platinum-based combination chemotherapy regimens in previously untreated patients. In the phase III EXTREME trial (Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer), 442 patients with recurrent or metastatic head and neck cancer were treated with platinum (either cisplatin or carboplatin) plus 5-FU with or without cetuximab.26 Patients with oral cancer were well-represented in this study, accounting for about 20% of the treatment population. In this study, chemotherapy was given for a maximum of 6 cycles, after which cetuximab could be continued as a single agent. This study found that the addition of cetuximab resulted in a significant improvement in overall survival, increased from 7.4 months to 10.1 months. Both progression-free survival and response rate were also increased. This improvement came without a significant increase in severe toxicity, and based on this data, cetuximab has been approved by the US Food and Drug Administration for use in the front-line treatment setting in combination with platinum and 5-FU–based chemotherapy. Panitumumab, a fully human monoclonal antibody also directed against the epidermal growth factor receptor, has been studied in the treatment of metastatic head and neck cancers. Currently, however, this agent does not have an established role in the treatment of head and neck cancer and has not been shown to improve survival when given with front-line cisplatin plus 5-FU chemotherapy.27 For patients with progression after front-line chemotherapy, multiple options exist. These include cytotoxic chemotherapy, programmed cell death (PD)-1 inhibitors,
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cetuximab, and small molecule tyrosine kinase inhibitors. Choice of treatment depends on prior treatment history, performance status, and the presence or absence of significant medical comorbid illnesses. There has been considerable excitement surrounding use of PD-1 inhibitors, which have been found recently to improve survival in this treatment setting. PD-1 is a receptor expressed on T cells, B cells, and natural killer cells. It functions, along with PD-ligand 1 (PD-L1) and PD-L2, to suppress immune function by downregulating the activity of effector T cells. PD-L1 and PD-L2 are expressed on many different cell types throughout the body and they are also expressed commonly on tumor cells. By taking advantage of this receptor–ligand complex, tumor cells can evade destruction by effector T cells. Many different monoclonal antibodies have been developed for the purpose of interfering with the PD-1/PD-L1 axis. These agents do not cause side effects commonly associated with chemotherapy, such as myelosuppression, nausea, vomiting, and fatigue. However, they can cause a variety of autoimmune toxicities, and although they are often well-tolerated as single agents, toxicity can occur suddenly and be severe, even potentially fatal, if not recognized and treated promptly. Common side effects include rash, diarrhea, hepatitis, thyroiditis, hypophysitis, and pneumonitis. Approved agents to date include nivolumab, pembrolizumab, and atezolizumab. Both nivolumab and pembrolizumab have shown activity in the treatment of recurrent and metastatic head and neck cancers and both are currently FDA approved for the treatment of metastatic head and neck cancer with progression after first-line platinum-containing chemotherapy. Nivolumab was studied in a phase III clinical trial that enrolled patients with platinum-refractory recurrent or metastatic disease. Notably, about one-half of the enrolled patients had metastatic oral cancers. It was compared with investigator’s choice of single-agent therapy, with options including cetuximab, methotrexate, and docetaxel.28 In this study, a total of 361 patients were treated and nivolumab improved overall survival from 5.1 months to 7.5 months. PD-L1 expression was measured in all patients, and it was found that, in patients with expression of 1% or higher, survival was improved with the use of nivolumab. The FDA approval of nivolumab does not require measurement of PD-L1 expression. It is given at a dose of 3 mg/kg intravenously every 2 weeks. Pembrolizumab, in contrast, was approved provisionally in August 2016 based on the results of a phase Ib clinical trial.29 This study enrolled 174 patients with progression on or after platinum-based chemotherapy. Initial results were notable for a 16% response rate, notably including 8 complete responses (5% of the population). Also, most responses (23 of 28) lasted longer than 6 months. Updated results presented in 2016 at the American Society of Clinical Oncology meeting were notable for median overall survival of 8 months and 12-month survival of 38%.30 This agent is currently FDA approved at a fixed dose of 200 mg given intravenously every 3 weeks, and also does not require measurement of tumor PD-L1 expression. Two phase III trials are ongoing to confirm these results. In addition to these monoclonal antibodies, cetuximab has modest activity in the treatment of recurrent or metastatic head and neck cancers. For example, in 1 series of 103 patients who had progression after previous treatment with platinum-based chemotherapy, it was associated with a response rate of 13% and a median survival of 7.5 months.31 Multiple small molecule tyrosine kinase inhibitors have been studied in the treatment of advanced head and neck cancer. These include gefitnib,32,33 afatinib,34 sunitinib,35 and erlotinib.36 To date, however, no study has found evidence of convincing activity or improvement in overall survival associated with these agents.
Chemotherapy for Oral Cancer
Various cytotoxic chemotherapy drugs have been studied in the second-line setting and beyond. Overall, studies have failed to document significant benefit and, to date, there is no study that has found evidence of improved survival associated with cytotoxic chemotherapy in the second-line setting or beyond. Agents that have been studied include methotrexate,33 gemcitabine,37 paclitaxel,38 docetaxel,39 and 5-FU.23 Choice of agent depends on prior treatment history and differences in expected toxicity between the agents, because there are no comparative studies to guide decision making. Given the limited available treatment options for patients with metastatic disease, particularly after second-line treatment with PD-1 inhibitor–based therapy, it is important to closely monitor symptoms and to discuss prognosis and goals of care. Recurrent and metastatic head and neck cancer carries the potential for considerable morbidity combined with short survival, and a transition away from active treatment and toward comfort care and hospice should be pursued when appropriate. REFERENCES
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Chemotherapy for Oral Cancer
27. Vermorken JB, Stohlmacher-Williams J, Davidenko I, et al. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncol 2013;14:697–710. 28. Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for recurrent squamouscell carcinoma of the head and neck. N Engl J Med 2016;375:1856–67. 29. US Food and Drug Administration (FDA). DA approval statement for pembrolizumab (Keytruda). Available at: https://www.fda.gov/drugs/informationondrugs/ approveddrugs/ucm515627.htm. Accessed April 13, 2017. 30. Mehra R, Seiwert TY, Mahipal A, et al. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC): pooled analyses after long-term follow-up in KEYNOTE-012. J Clin Oncol 2016; 34(Suppl 15); abstr 6012. 31. Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 2007;25: 2171–7. 32. Cohen EE, Kane MA, List MA, et al. Phase II trial of gefitinib 250mg daily in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res 2005;11:8418–24. 33. Stewart JS, Cohen EE, Licitra L, et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J Clin Oncol 2009;27:1864–71. 34. Machiels JP, Haddad RI, Fayette J, et al. Afatinib versus methotrexate as secondline treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head&Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol 2015;16:583–94. 35. Machiels JP, Henry S, Zanetta S, et al. Phase II study of sunitinib in recurrent or metastatic squamous cell carcinoma of the head and neck: GORTEC 2006-01. J Clin Oncol 2010;28:21–8. 36. Soulieres D, Senzer NN, Vokes EE, et al. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2004;22:77–85. 37. Catimel G, Vermorken JB, Clavel M, et al. A phase II study of Gemcitabine (LY 188011) in patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group. Ann Oncol 1994;5:543–7. 38. Grau JJ, Caballero M, Verger E, et al. Weekly paclitaxel for platin-resistant stage IV head and neck cancer patients. Acta Otolaryngol 2009;129:1294–9. 39. Guardiola E, Peyrade F, Chaigneau L, et al. Results of a randomised phase II study comparing docetaxel with methotrexate in patients with recurrent head and neck cancer. Eur J Cancer 2004;40:2071–6.
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